The goal of this project is to identify genes responsible for human breast cancer. Our strategy is to map genes for inherited susceptibility to breast cancer in very high risk families. Our results will be applicable to the etiology of breast cancer in general, because high-risk families serve as a model for breast cancer in the population as a whole. Genes that are altered in high-risk families exist as normal sequences in 11 women. In breast epithelial cells, these genes are subject to attack by environmental carcinogens. Therefore, changes in these sequences may cause breast cancer in women who have no inherited susceptibility. Thus, identifying genes for inherited breast cancer may reveal genes crucial to environmentally-induced breast cancer as well. Our recent studies in genetic epidemiology suggest that increased breast cancer risk associated with family history is due to very severe risk in a small number of families, rather than modestly increased risk in many families. Our results also indicate that susceptibility in these high-risk families is inherited as an autosomal dominant gene with high penetrance and no polygenic influence. In these high-risk families, we test whether breast cancer susceptibility is due to inherited variation in genes that may be involved in breast tumorigenesis: hormone and growth factor receptors, human homologue to MMTV and its integration sites, and oncogenes. We screen for restriction fragment length polymorphisms in these candidate sequences, then use each sequence as a marker for linkage analysis of breast cancer in families. Concurrently, we are using 201 polymorphic random probes on all autosomes to map susceptibility genes in these families, focusing first on minisatellites and probes with variable numbers of tandem repeats and on probes from chromosomal regions associated with cytogenetic alterations in breast tumors. The goal of gene mapping using random probes is to locate a marker closely linked to breast cancer susceptibility, then identify the gene by macrorestriction mapping and chromosome walking techniques. Two small epidemiologic studies will accompany our gene mapping project. First, we will test whether any lifestyle factors protect against expression of breast cancer among susceptible women, by comparing breast cancer patients in our families to their genetic- ally susceptible, but unaffected female relatives. Second, we will explore whether hormonally-related risk factors for breast cancer can be expressions of genetic susceptibility by comparing susceptible and non-susceptible women in the families.